U.S. patent application number 16/945990 was filed with the patent office on 2021-02-11 for expandable hemostat composed of oxidized cellulose.
The applicant listed for this patent is Ethicon, Inc., Omrix Biopharmaceuticals Ltd.. Invention is credited to HADAS ALPERIN, TAMAR AUERBACH-NEVO, OMRI FAINGOLD, EREZ ILAN, Dwayne Looney, TALI NEGREANU-GILBOA, Yi-Lan Allen Wang.
Application Number | 20210038757 16/945990 |
Document ID | / |
Family ID | 1000005022507 |
Filed Date | 2021-02-11 |
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United States Patent
Application |
20210038757 |
Kind Code |
A1 |
ILAN; EREZ ; et al. |
February 11, 2021 |
EXPANDABLE HEMOSTAT COMPOSED OF OXIDIZED CELLULOSE
Abstract
An expandable biodegradable hemostatic matrix comprised of
oxidized cellulose, and having a density ranging from about 0.8 to
about 1.2 gr/cm.sup.3 is disclosed herein. The matrix may be
expandable to at least 3 times its original volume within 4 sec
upon contact with an aqueous solution room temperature. Further
disclosed are methods for making the hemostatic matrix as well as
method of treating a wound.
Inventors: |
ILAN; EREZ; (Kibbutz Netzer
Sereni, IL) ; FAINGOLD; OMRI; (Rehovot, IL) ;
AUERBACH-NEVO; TAMAR; (Rehovot, IL) ;
NEGREANU-GILBOA; TALI; (Givatayim, IL) ; ALPERIN;
HADAS; (Tel-Aviv, IL) ; Wang; Yi-Lan Allen;
(Belle Mead, NJ) ; Looney; Dwayne; (Flemington,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Omrix Biopharmaceuticals Ltd.
Ethicon, Inc. |
Rehovot
Somerville |
NJ |
IL
US |
|
|
Family ID: |
1000005022507 |
Appl. No.: |
16/945990 |
Filed: |
August 3, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62883764 |
Aug 7, 2019 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 15/28 20130101;
A61L 15/425 20130101; A61L 15/64 20130101; A61L 15/44 20130101 |
International
Class: |
A61L 15/28 20060101
A61L015/28; A61L 15/42 20060101 A61L015/42; A61L 15/64 20060101
A61L015/64; A61L 15/44 20060101 A61L015/44 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 7, 2019 |
IL |
268572 |
Claims
1. A biodegradable hemostatic matrix comprising oxidized cellulose
(OC), said OC comprising one or more sheets, wherein said matrix:
(i) has a density ranging from about 0.8 to about 1.2 gr/cm.sup.3,
and (ii) is expandable to at least 3 times its original volume
within 4 sec upon contact with an aqueous solution at at-least one
temperature between 10 and 40.degree. C.
2. The matrix of claim 1, being in a compressed state.
3. The matrix of claim 1, being capable of expanding to at least
90% of its maximum expansion capacity within 30 seconds following
immersion in an aqueous solution.
4. The matrix of claim 3, being expandable to 15 to 30 times its
original volume within 4 sec upon contact with an aqueous solution
at at-least one temperature between 10 and 30.degree. C.
5. The matrix of claim 1, wherein said OC comprises oxidized
regenerated cellulose (ORC).
6. The matrix of claim 5, wherein said ORC is in the form of a
non-woven fabric.
7. The matrix of claim 1, further comprising one or more additives
selected from the group consisting of calcium salt, anti-infective
agent, and hemostasis promoting agent.
8. The matrix of claim 1, further comprising one or more excipients
selected from the group consisting of sodium chloride, mannitol,
albumin, and sodium acetate.
9. The matrix of claim 1, wherein the carboxyl content of the OC
ranges from 12% to 21%, by weight, per United States Pharmacopeia
(USP) 23-NF18.
10. The matrix of claim 1, having a pre-expansion total surface
area ranging from about 0.5 to about 10 cm.sup.2, optionally, about
3 to about 5 cm.sup.2, optionally, having a pre-expansion volume
ranging from about 0.05 cm.sup.3 to about 2 cm.sup.3, optionally
about 0.4 to about 0.8 cm.sup.3.
11. The matrix of claim 1, produced by compressing an OC-based
material by applying on a surface thereof a pressure ranging from
0.3 to 7 ton/cm.sup.2.
12. The matrix of claim 1, wherein the OC comprises less than 8%
water, optionally less than 5% water, prior to the contact with the
aqueous solution.
13. The matrix of claiml, being expandable to at least 4 times its
original volume within 4 sec upon contact with an aqueous solution
at at-least one temperature between 10 and 40.degree. C.
14. The matrix of claim 1, being expandable to at least 5 times its
original volume within 4 sec upon contact with an aqueous solution
at at-least one temperature between 10 and 40.degree. C.
15. The matrix of claim 1, being expandable to 3 to 6 times its
original volume within 4 sec upon contact with an aqueous solution
at at-least one temperature between 10 and 40.degree. C.
16. A method of making the hemostatic matrix of any one of claim 1,
the method comprising the step of compressing an OC-based material
by applying on a surface thereof a pressure ranging from about 0.3
to about 7 ton/cm.sup.2.
17. The method of claim 16, wherein said OC material comprises
ORC.
18. The method of claim 17, wherein said ORC is in the non-woven
form.
19. The method of claim 16, further comprising the step of mixing
the OC material with one or more additives selected from the group
consisting of calcium salt, anti-infective agent, and hemostasis
promoting agent.
20. A method of treating a wound comprising the step of applying
the biodegradable hemostatic matrix of claim 1 onto and/or into the
wound of a subject in a need thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates, inter alia, to expandable
biodegradable hemostatic matrix of oxidized cellulose (OC) and uses
thereof e.g., for treating a wound.
BACKGROUND OF THE INVENTION
[0002] In a wide variety of circumstances, animals, including
humans, can suffer from bleeding due to wounds or during surgical
procedures. In some circumstances, the bleeding is relatively minor
and normal blood clotting functions, so the application of simple
first aid is all that is required. In other circumstances
substantial bleeding can occur. These situations usually require
specialized equipment and materials as well as personnel trained to
administer appropriate aid.
[0003] Conventional methods to achieve hemostasis include the use
of surgical techniques, sutures, ligatures or clips, and
energy-based coagulation or cauterization. When these conventional
measures are ineffective or impractical, adjunctive hemostasis
techniques and products are required.
[0004] The selection of appropriate methods or products for the
control of bleeding is dependent upon many factors, which include
but are not limited to bleeding severity, anatomical location of
the source and the proximity of adjacent critical structures,
whether the bleeding is from a discrete source or from a broader
surface area, visibility and precise identification of the source
and access to the source.
[0005] In an effort to address the above-described problems,
materials have been developed for controlling excessive bleeding.
Topical Absorbable Hemostats (TAHs) are widely used in surgical
applications. TAHs encompass products based on oxidized cellulose
(OC), gelatin, collagen, chitin, chitosan, etc. To improve the
hemostatic performance, scaffolds based on the above materials can
be combined with biologically-derived clotting factors, such as
thrombin and fibrinogen.
[0006] Due to its biodegradability, and its bactericidal and
hemostatic properties, oxidized cellulose (OC)-based materials,
such as oxidized regenerated cellulose (ORC), have long been used
as topical hemostats in a variety of surgical procedures, including
neurosurgery, abdominal surgery, cardiovascular surgery, thoracic
surgery, head and neck surgery, pelvic surgery and skin and
subcutaneous tissue procedures. Several methods for forming various
types of hemostats based on OC materials are known, whether made in
powder, woven, non-woven, knit, and other forms. Currently utilized
hemostats include powder, or fabrics comprising ORC.
[0007] Fast management of rapid bleeding is crucial for surgical
procedures. Hemostasis can be achieved by a variety of methods. A
common practice is the use of manual compression in which pressure
is applied on the wound through a bandage or a hemostatic patch to
facilitate the formation of a clot. Manual compression has some
notable disadvantages: it is considerably cumbersome and relatively
time consuming for the surgical staff. Regarding its application,
manual compression is not effective in cases in which blood is lost
from narrow and hard-to-reach spaces, gaps, or cavities. In such
cases, a flowable sealant is commonly applied through a conducting
applicator that is used to achieve hemostasis. A line of flowable
sealant products are available in the market, most of them are
based on biologically active components.
[0008] Biological hemostats carry a potential risk of contamination
and their costs are high. Further, several hemostats in the market
require laborious preparation before applying, a degree of
expertise from the surgical staff and they lack the required
efficacy in cases of rapid blood loss.
[0009] U.S. Patent Application having Publication No. 2012/0101520
relates to apparatus and methods used to seal a vascular puncture
site, particularly sites of punctures that are the result of
catheterization or other interventional procedures. The sealing
device includes a sealing member and a tether. The sealing member
occupies a space in an incision, puncture, or other wound and
sealing the space that it occupies, to prevent further blood flow.
The tether is attached to the sealing member, and provides the user
with the ability to withdraw the sealing member if necessary.
[0010] U.S. Pat. No. 8,518,064 relates generally to a method for
anchoring an expandable biocompatible plug material to a vessel
wall to form an anchored occluding plug blocking or reducing blood
flow to a desired vessel target, such as an artery supplying blood
to a neoplastic tissue or tumor.
[0011] U.S. Patent Application having Publication No. 2005/0287215
discloses a plurality of packed particles that contain interstitial
pores, where the interstitial pores have a pore volume and a median
pore diameter effective to provide improved absorption of
physiological fluids or an aqueous media when placed in contact
therewith, compared to a plurality of unpacked particles of the
same material, where the particles are made of a biocompatible
material and have an average diameter suitable for use in providing
hemostasis to a site of a body of a mammal requiring hemostasis,
hemostatic compositions containing such plurality of packed
particles, methods of making such particles and compositions and
medical devices suitable for delivering and containing the
hemostatic plurality of particles and/or composition to a site of a
body.
[0012] U.S. Patent Application having Publication No. 2014/0142523
discloses, inter alia, self-expanding wound dressings that include
a first outer layer, a second outer layer, and a liquid-expandable
layer disposed between the first outer layer and the second outer
layer, wherein the liquid-expandable layer includes a plurality of
liquid-expandable articles retained by a substrate, wherein the
plurality of liquid-expandable articles expand to form expanded
articles upon contact with a liquid.
[0013] U.S. Pat. No. 8,828,050 relates to hemostatic composition
comprising a plurality of liquid expandable articles capable of
expanding upon contact with a liquid. A suitable composition
comprises a plurality of liquid-expandable articles that may be
mechanically uncoupled from one another and therefore may be
capable of moving independently from one another. The plurality of
liquid-expandable articles may comprise a compressed material
capable of a high-degree of expansion upon liquid contact.
[0014] U.S. Patent Application having Publication No. 2007/0014862
discloses, inter alia, a hemostatic agent comprising oxidized
cellulose in the form of a compressible, shapeable mass that can
remain substantially in the compressed or shaped form for placement
on a bleed site or into a wound gap. The oxidized cellulose may be
a pellet of unwoven oxidized cellulose fibrous strands, or it may
be strands of unwoven cellulose fibers woven or otherwise arranged
into a gauze or mesh. The pellet may be compressed before being
applied to the wound, which thereby allows the pellet to expand to
conform to the shape of the wound gap. The pellet may be allowed to
remain in the wound gap during the healing of the wound, thus
causing the pellet to be absorbed by the biological processes of
the body.
[0015] U.S. Patent Application having Publication No. 2006/0078589
discloses a device for treating oral wounds that form a gap and
hence too large to suture. The device is intended to fill the
resulting wound gap and upon contact with bleeding tissues cause
local hemostasis. The device will remain in and protect the wound
gap during the healing process.
[0016] However, since control of bleeding is essential and critical
in surgical procedures to minimize blood loss, to reduce
post-surgical complications, and to shorten the duration of the
surgery in the operating room, there is a need of improved
hemostatic forms and materials which facilitate ease of
application, especially in hard-to-reach bleeding sites.
SUMMARY OF THE INVENTION
[0017] The invention relates, inter alia, to an expandable hemostat
matrix constructed from compressed oxidized cellulose (OC) such as
oxidized regenerated cellulose (ORC), which may be used e.g., for
achieving hemostasis in case of a puncture wound or a tissue gap.
The hemostatic oxidized cellulose material can rapidly expand when
exposed to body fluid, and following absorption with blood, the
disclosed matrix can reduce the bleeding without further applying
external compression, and may take on the shape of the wound site
enabling hemostasis. The matrix may be left at the wound site as it
dissolves over time. The matrix may be produced from the
compression of different textured OC or ORC material (for example,
non-woven, and knitted).
[0018] The common practice of manual compression is considerably
cumbersome and relatively time consuming for the surgical staff the
common practice, and is not effective in cases in which blood is
lost from narrow and hard-to-reach spaces.
[0019] In sharp distinction, the disclosed expandable matrix may be
effective as an immediate solution for treating blood loss injuries
in which manual compression is not feasible or effective. Thus, the
matrix allows to overcome the disadvantages of common practice of
manual compression in which pressure is applied on the wound
through a bandage or a hemostatic patch to facilitate the formation
of a clot.
[0020] The matrix has further notable advantages over existing
solutions: not requiring preparation time, stable at room
temperature (RT), cost-effective and safety over biological
hemostats.
[0021] In the Examples section below it is further demonstrated
that the disclosed matrix comprising ORC non-woven material
exhibits superior expansion characteristics and hemostasis efficacy
as compared to a tablet composed of an ORC knitted source material
and powder.
[0022] Accordingly, the expandable matrix is also effective as an
immediate solution for treating blood loss injuries, for example,
for dental procedures with strong bleeding. Furthermore, to acting
as an efficient hemostat, ORC is a bactericidal compound, which is
advantageously following an intervention in a body cavity, such as
the mouth which holds a high concentration of bacteria.
[0023] According to an aspect of the present invention, there is
provided a biodegradable hemostatic matrix comprising oxidized
cellulose (OC), wherein said matrix: (i) has a density ranging from
about 0.8 to about 1.2 gr/cm.sup.3, and (ii) is expandable to at
least 3 times, least 4 times, or least 5 times its original volume
within 4 sec upon contact with an aqueous solution at at-least one
temperature between 10 and 40.degree. C. In some embodiments, the
matrix has a density of about 1.2 gr/cm.sup.3.
[0024] In some embodiments, the OC in the matrix comprises or is in
the form of one or more sheets, e.g., fibrous and/or packed layered
sheets.
[0025] In some embodiments, the matrix has a volume greater than 5
mm.sup.3, e.g., 0.3 to 0.9 cm.sup.3.
[0026] In some embodiments, the matrix is in a compressed form. In
some embodiments, the matrix is in the pre-expanded state or
form.
[0027] The term "compressed" may refer to being compressed in one
or more directions, e.g., by horizontal, vertical and/or radial
compressive forces.
[0028] In some embodiments, the matrix is substantially in a
cylindrical, rectangular, and/or polygonal shape.
[0029] In some embodiments, the matrix is capable of expanding to
at least 90% of its maximum expansion capacity within 30 seconds
following immersion in an aqueous solution, and is expandable to 3
to 30, or 15 to 30 times its original volume within 4 sec upon
contact with an aqueous solution at at-least one temperature
between 10 and 30.degree. C.
[0030] In some embodiments, the matrix is in the form of an article
selected from a tablet and a wound dressing.
[0031] In some embodiments, the matrix the OC comprises oxidized
regenerated cellulose (ORC).
[0032] In some embodiments, the OC matrix originates from an OC-
(or ORC-) based material having the form selected from: knitted
fabric, non-woven fabric, woven fabric, a shredded material, and
any combination thereof.
[0033] In some embodiments, the ORC-based material is in the form
of a non-woven fabric.
[0034] In some embodiments, the matrix further comprises one or
more additives selected from calcium salt, anti-infective agent,
and hemostasis promoting agent.
[0035] In some embodiments, the matrix further comprises one or
more excipients selected from sodium chloride, mannitol, albumin,
and sodium acetate.
[0036] In some embodiments, the carboxyl content of the OC ranges
from 12% to 21%, by weight, per United States Pharmacopeia (USP)
23-NF18.
[0037] In some embodiments, the matrix in the pre-expansion form
has a total surface area ranging from about 3 to about 5
cm.sup.2.
[0038] In some embodiments, the matrix has a pre-expansion volume
ranging from about 0.4 to about 0.8 cm.sup.3.
[0039] In some embodiments, the matrix is for use in controlling
bleeding in soft tissues.
[0040] In some embodiments, the matrix is for use in inhibiting or
reducing the formation of load of a microorganism.
[0041] In some embodiments, the matrix is produced by compressing
an OC-based material by applying on at least one surface thereof a
pressure ranging from 0.3 to 7 ton/cm.sup.2, e.g., 0.3 to 2.5
ton/cm.sup.2.
[0042] According to an aspect of the present invention, there is
provided a method of making the hemostatic matrix in any embodiment
thereof, the method comprising the step of compressing an OC-based
material by applying on at least one surface thereof a pressure
ranging from about 0.3 to about 7 ton/cm.sup.2.
[0043] In some embodiments of the method of making the hemostatic
matrix, the OC material comprises ORC.
[0044] In some embodiments of the method of making the hemostatic
matrix, the ORC is in the non-woven form.
[0045] In some embodiments of the method of making the hemostatic
matrix, the method further comprises the step of mixing the OC
material with one or more additives selected from calcium salt,
anti-infective agent, and hemostasis promoting agent.
[0046] According to an aspect of the present invention, there is
provided a method of treating a wound comprising the step of
applying the disclosed biodegradable hemostatic matrix of any
embodiment thereof onto and/or into the wound of a subject in a
need thereof.
[0047] Unless otherwise defined, all technical and/or scientific
terms used herein have the same meaning as commonly understood by
one of ordinary skill in the art to which the invention pertains.
Although methods and materials similar or equivalent to those
described herein can be used in the practice or testing of
embodiments of the invention, exemplary methods and/or materials
are described below. In case of conflict, the patent specification,
including definitions, will control. In addition, the materials,
methods, and examples are illustrative only and are not intended to
be necessarily limiting.
BRIEF DESCRIPTION OF THE DRAWINGS
[0048] Some embodiments of the invention are herein described, by
way of example only, with reference to the accompanying drawings.
With specific reference now to the drawings in detail, it is
stressed that the particulars shown are by way of example and for
purposes of illustrative discussion of embodiments of the
invention. In this regard, the description taken with the drawings
makes apparent to those skilled in the art how embodiments of the
invention may be practiced.
[0049] FIGS. 1A-1B present photographs showing the disclosed matrix
in the form of a pellet, with different sizes; large (FIG. 1A), and
small (FIG. 1B); numbers in rulers are in centimeters.
[0050] FIG. 2 presents photographs demonstrating the application of
the disclosed matrix in the form of a pellet during a surgical
procedure: the white pellet is inserted to a bleeding site (left
panel) and thereafter absorbs blood and expands rapidly to from its
original volume to facilitate efficient hemostasis (right panel,
following the arrow).
[0051] FIGS. 3A-3B present bar graphs showing the maximal expansion
volume (cm.sup.3) in saline of various oxidized regenerated
cellulose (ORC) matrix samples as described in the Examples section
(Table 2A), compressed under a 0.5, 2, and 5-ton compression
strength (T) (FIG. 3A); and respective times (in sec) taken for
each sample to reach maximal expansion (FIG. 3B). In each bar
triplet, the left one refers to 0.5 Ton (T), the middle one refers
to 1 T, and the right one refers to 5 T.
[0052] FIGS. 4A-4C present bar graphs based on data presented in
Table 2B showing the expansion volume in saline of various ORC
matrix samples and for the Gauze pad (non-oxidized cellulose)
compressed under different forces ranging from 0.25 to 5 ton
(compression strength; T) as: expansion factor after 4 sec (FIG.
4A); maximal expansion factor (FIG. 4B); and combined bars of
maximal expansion factor and expansion factor after 4 sec for the
tested ORC materials (FIG. 4C).
[0053] FIG. 5 presents a graph showing the ORC materials density
vs. the expansion factor after 4 sec in saline.
[0054] FIG. 6 presents a graph showing the ORC materials density
vs. the maximal expansion factor in saline.
[0055] FIG. 7 presents images showing a schematic illustration of
bleeding levels grade used in the spleen biopsy punch model. The
white circle represents the punch, the grey circle represents
background the tissue and the black circle represents the blood
flowing from the biopsy punch site (from left panel to right: No
Bleeding "0"; Ooze "1"; Very Mild "2"; Mild "3"; Moderate "4";
Severe "5").
DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0056] An object of the present invention is to provide a hemostat
matrix composition comprising oxidized cellulose (OC) e.g.,
oxidized regenerated cellulose (ORC) having a certain range of
density, capable of high-degree of expansion upon contact with body
fluids, which may easily be applied to a site of need e.g., for
achieving hemostasis in case of a puncture wound or a tissue gap.
An advantage of the expandable composition as described herein is
the ability to quickly expand into expanded form. This allows the
expanded composition to quickly fill the wound cavity and provide a
nearly immediate hemostatic effect without the need for applying
any external pressure or compression. Additional advantages
associated with the present invention include, inter alia, improved
positioning within the wound, improved tissue apposition and better
conformation to intricate wound contours.
[0057] As explained in more detail below, the disclosed composition
can be applied to a bleeding tissue and thereafter can rapidly
expand upon exposing to body fluid, while taking on the shape of
the wound site, enabling to assist in hemostasis. The composition
can be left at the wound site as it degrades over time.
[0058] "Hemostasis" (or "haemostasis") refers to the first stage of
wound healing. It is a process which causes bleeding to stop. By
"assist in hemostasis" it is meant to help reduce or stop bleeding.
By "applied to a bleeding tissue" it is meant to refer to a topical
application of the composition at the bleeding site, e.g., at a
surgical site to control bleeding. Control of bleeding is needed in
various situations including treatment of wounds, or during
surgical procedures, such as, for example, laparoscopic surgery,
neurosurgery, abdominal surgery, cardiovascular surgery, thoracic
surgery, head and neck surgery, pelvic surgery and skin and
subcutaneous tissue procedures. For at least one of these
situations, the composition of the invention may serve as a
suitable sealant.
[0059] In some embodiments, the composition comprises compressed
OC. In some embodiments, the OC is compressible.
[0060] The term "compressed", or "compressed state", refers to the
state of a material subsequent to compression e.g., by applying a
pressure thereon. Conversely, the term "uncompressed" refers to the
state of a material prior to compression, or upon expansion e.g.,
subsequent to its degradation or explosion. The term "compressible"
refers to the ability of a material to undergo compression.
[0061] In some embodiments, the composition, being in a dry state,
remains substantially in the compressed or shaped form prior to
contact or placement in/on aqueous media such as in a bleeding site
or in a wound gap.
[0062] The term "compressed state" is also referred to herein as
"original volume".
[0063] In some embodiments, the compressed material, upon exposure
to liquid, e.g., an aqueous solution, may rapidly expand as
described herein, without using exogenous gases or pressure. By
"aqueous solution" it is meant to encompass both water as well as a
solution in which the solvent is or comprises water, e.g., saline,
and body fluids, such as blood. The water may refer to pure
water.
[0064] The compressed matrix so formed exhibit improved expansion
and/or liquid (e.g., water)-swellability when compared to
particles, e.g., milled ORC particles. Compositions of the present
invention may be applied as is in a bleeding site, or in some
embodiments, be applied together with saline, simultaneously or
sequentially. In some embodiments, the matrix may be applied
manually, or, in some embodiments, using a device such as a medical
device, e.g., trocar (of various dimensions e.g., a diameter of 5,
10, 12, 15 mm, including any value therebetween), or other known
applicators. Depending on shape, form and size desired for the
contemplated use, different molds or other compression techniques
may be used to achieve the desired body of the disclosed matrices
or compositions.
[0065] Embodiments of the present invention further relate, inter
alia, to fast swelling, and superabsorbable, biodegradable
hemostatic composition. The fast swelling may be provided upon
contact with plasma, allowing the composition to absorb at least
some, or even most of plasma components.
[0066] The term "absorb", or any inflection thereof, refers to the
physical state in which the fluid (e.g., aqueous media such as body
fluid) is distributed throughout the inner body of the OC
matrix.
[0067] Upon contact and swelling, e.g., up to 2, 3, 4, 5, 6, 7, 8,
9, 10, or even to more than up to 20 times of the dry composition,
the disclosed composition allows to fill up e.g., a confined wound
space to simulate tamponade effect and enhance the natural clotting
process. In some embodiments, the disclosed composition is
flexible, thereby ensuring its access to narrow spaces and its
application to uneven surfaces, making it a useful material to
address the intra-operational bleeding or oozing. The instant
matrix is particularly suitable for hard-to-access wounds such as
tissue crevice or cavity bleeding.
[0068] By "dry" it is meant to refer to OC or ORC comprising less
than 8%, less than 5%, or less than 1%, of water, by weight.
[0069] The term "flexible" in the context of the disclosed matrix
(e.g., in the form of a tablet or pellet) pertains to a material
which may be bent or rolled without breaking.
[0070] According to an aspect of the present disclosure, there is
provided a biodegradable hemostatic matrix comprising oxidized
cellulose (OC), wherein the matrix: (i) has a density ranging from
about 0.8 to about 1.2 gr/cm.sup.3, and (ii) is expandable to at
least 3 times its original volume within 4 sec upon contact with an
aqueous solution at at-least one temperature between 10 and
40.degree. C.
[0071] In some embodiments, the matrix is in the form of an article
selected from, without being limited thereto, a tablet and a
pellet.
[0072] As used herein, the term "fabric" relates to a flexible
material typically comprising a network of fibers produced by, for
example and without limitation, weaving, knitting, crotcheting,
knotting, felting or bonding. Typically, but not exclusively,
"gauze" relates to thin, typically loosely woven cloth used for
dressings and swabs or to any material made of an open, mesh-like
weave.
[0073] In some embodiments, the OC comprises or is in the form of
one or more sheets. The term "sheet" means a material that is thin
in comparison to its length and breadth. In some embodiments, the
sheets form a substantially flat configuration. In some
embodiments, the sheet has a non-planar configuration. In some
embodiments, the sheets are configured in a compressed position. In
some embodiments, the OC is not in the form of powder or a
plurality of particles. In some embodiments, the OC is not milled.
By the term "OC is not in the form of powder or a plurality of
particles" it is meant that: less than 50%, less than 40%, less
than 30%, less than 20%, less than 10%, or even essentially no OC
in the disclosed matrix, by weight, is or comprises a powdered form
and milled particles; or at least 50%, at least 60%, at least 70%,
at least 80%, at least 90%, or even essentially all OC in the
disclosed matrix, by weight, is or comprises a powdered form and
milled particles.
[0074] In some embodiments, by "expandable" it is meant to refer to
a structure being capable of reaching larger volume than its
initial volume upon exposure, contact with, or immersion in an
aqueous solution such as water. The term "expandable" may refer to
one or more directions in which the matrix may expand, e.g.,
radially expandable. As used herein, the term "radially expandable"
includes segments that can be converted from a small configuration
to a radially expanded, typically in cylindrical configuration. The
term "expandable" may further refer to horizontally expandable
(i.e. the width is increased), or vertically expandable (i.e. the
height is increased). "Small configuration" may refer to at least
one dimension, e.g., a diameter.
[0075] Additionally or alternatively, the term "expandable" may
further refer to being either or both horizontally expandable and
vertically expandable. Additionally or alternatively, the term
"expandable" may further refer to being horizontally expandable,
vertically expandable and/or radially expandable.
[0076] In some embodiments, the composition is expandable to at
least 2, at least 3, at least 4, at least 5, at least 6, or at
least 7 times, its original volume upon contact with an aqueous
solution. In some embodiments, the composition is expandable to
about 2, about 3, about 4, about 5, about 6, or about 7 times, its
original volume, upon contact with an aqueous solution, including
any value and range therebetween. In some embodiments, the
composition is expandable to 2 to 5, 3 to 6, or 4 to 7, its
original volume, including any value and range therebetween.
[0077] In some embodiments, the matrix is expandable to at least 2,
at least 3, at least 4, at least 5, at least 6, or at least 7
times, its original volume within 2 to 6 sec, or 3 to 5, e.g., 4
sec upon contact with an aqueous solution at around room
temperature.
[0078] In some embodiments, the matrix is expandable to 3 to 40, or
10 to 40 times its original volume within 2 to 6 sec, or 3 to 5,
e.g., 4 sec upon contact with an aqueous solution at around room
temperature. In some embodiments, the matrix is expandable to 15 to
30 times, its original volume within 2 to 6 sec, or 3 to 5, e.g., 4
sec upon contact with an aqueous solution at around room
temperature.
[0079] In some embodiments, the matrix is expandable to 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, or 30 times, its original volume, including
any value and range therebetween, within 2 to 6 sec, or 3 to 5,
e.g., 4 sec upon contact with an aqueous solution at around room
temperature.
[0080] Reference is made to the results presented in Table 2B,
which are further illustrated in FIGS. 4A to 6, demonstrating that
an ORC density of about 0.95 to 1.2 gr/cm.sup.3 provides optimal
expansion after 4 sec, with the "FIBRILLAR" and "SNoW" exhibiting
the highest expansion factor.
[0081] In some embodiments, the matrix comprises non-woven OC,
expandable to at least 5 times its original volume within 4 sec
upon contact with an aqueous solution at around room
temperature.
[0082] In some embodiments, the matrix comprises OC, has a density
of about 0.9 to about 1.25 gr/cm.sup.3 and is expandable to at
least 5 times its original volume within 4 sec upon contact with an
aqueous solution at around room temperature. In some embodiments,
the matrix comprises OC, has a density of 0.9 to about 1.25
gr/cm.sup.3 and is expandable to about 5 to about 6 its original
volume within 4 sec upon contact with an aqueous solution at around
room temperature.
[0083] In some embodiments, the matrix comprises non-woven OC, has
a density of about 0.9 to about 1.25 gr/cm.sup.3 and is expandable
to at least 5 times its original volume within 4 sec upon contact
with an aqueous solution at around room temperature. In some
embodiments, the matrix comprises non-woven OC, has a density of
about 0.9 to about 1.25 gr/cm.sup.3 and is expandable to about 5 to
about 6 its original volume within 4 sec upon contact with an
aqueous solution at around room temperature.
[0084] In some embodiments, the matrix comprises OC, has a density
of about 1 to about 1.25 gr/cm.sup.3 and is expandable to at least
6 times its original volume within 4 sec upon contact with an
aqueous solution at around room temperature. In some embodiments,
the matrix comprises non-woven OC, has a density of about 0.9 to
about 1.25 gr/cm.sup.3 and is expandable to about 6 to about 8 its
original volume within 4 sec upon contact with an aqueous solution
at around room temperature.
[0085] In some embodiments, the matrix comprises non-woven OC, has
a density of about 1 to about 1.25 gr/cm.sup.3 and is expandable to
at least 6 times its original volume within 4 sec upon contact with
an aqueous solution at around room temperature. In some
embodiments, the matrix comprises non-woven OC, has a density of
about 0.9 to about 1.25 gr/cm.sup.3 and is expandable to about 6 to
about 8 its original volume within 4 sec upon contact with an
aqueous solution at around room temperature.
[0086] In some embodiments, the matrix comprises non-woven OC, has
a density of about 0.9 to about 1.25 gr/cm.sup.3 and is expandable
to at least 5 times its original volume within 4 sec upon contact
with an aqueous solution at around room temperature. In some
embodiments, the matrix comprises non-woven OC, has a density of
about 0.9 to about 1.25 gr/cm.sup.3 and is expandable to about 5 to
about 6 its original volume within 4 sec upon contact with an
aqueous solution at around room temperature.
[0087] In some embodiments, the matrix comprises OC, has a density
of about 1 to about 1.25 gr/cm.sup.3 and is expandable to at least
4 times its original volume within 4 sec upon contact with an
aqueous solution at around room temperature. In some embodiments,
the matrix comprises woven OC, has a density of about 1 to about
1.25 gr/cm.sup.3 and is expandable to at least 4 times its original
volume within 4 sec upon contact with an aqueous solution at around
room temperature. In some embodiments, the matrix comprises woven
OC, has a density of about 0.9 to about 1.25 gr/cm.sup.3 and is
expandable to about 4 to about 5 its original volume within 4 sec
upon contact with an aqueous solution at around room
temperature.
[0088] By "around the room temperature" it is meant to refer to at
least one temperature value within the range of 10 to 40.degree.
C., or e.g., 15 to 37.degree. C., e.g., 10, 15, 20, 25, 30, 35, 37,
or 40.degree. C., including any value and range therebetween.
[0089] In some embodiments, the matrix is capable of expanding to
at least 70%, at least 80%, or at least 90% of its maximum
expansion capacity within 20 to 40 seconds following immersion in
an aqueous solution. In some embodiments, the matrix is capable of
expanding to at least 70%, at least 80%, or at least 90% of its
maximum expansion capacity within 20 to 40 seconds following
immersion in an aqueous solution. In some embodiments, the matrix
is capable of expanding to at least 70% of its maximum expansion
capacity within 20 to 40 seconds following immersion in an aqueous
solution. In some embodiments, the matrix is capable of expanding
to at least 80% of its maximum expansion capacity within 20 to 40
seconds following immersion in an aqueous solution. In some
embodiments, the matrix is capable of expanding to at least 90% of
its maximum expansion capacity within 20 to 40 seconds following
immersion in an aqueous solution. In some embodiments, the matrix
is capable of expanding to 70 to 95% of its maximum expansion
capacity within 20 to 40 seconds following immersion in an aqueous
solution.
[0090] In some embodiments, the matrix is capable of expanding to
at least 70%, at least 80%, or at least 90% of its maximum
expansion capacity within about 30 seconds following immersion in
an aqueous solution. In some embodiments, the matrix is capable of
expanding to at least 70% of its maximum expansion capacity within
about 30 seconds following immersion in an aqueous solution. In
some embodiments, the matrix is capable of expanding to at least
80% of its maximum expansion capacity within about 30 seconds
following immersion in an aqueous solution. In some embodiments,
the matrix is capable of expanding to at least 90% of its maximum
expansion capacity within about 30 seconds following immersion in
an aqueous solution. In some embodiments, the matrix is capable of
expanding to 70 to 95% of its maximum expansion capacity within
about 30 seconds following immersion in an aqueous solution.
[0091] The term "expansion" means an increase in the volume. The
terms "expansion capacity", "maximum expansion" or "maximum
expansion capacity", which may be used interchangeably, mean the
maximal volume the matrix can reach following contact with aqueous
media.
[0092] In some embodiments, the matrix has a pre-expansion volume
ranging from about 0.4 to about 1.5 cm.sup.3, or from about 0.4 to
about 1.5 cm.sup.3. In some embodiments, the matrix has a
pre-expansion volume ranging from about 0.5 to about 0.75 cm.sup.3.
In some embodiments, the matrix has a pre-expansion volume of about
0.4, about 0.5, about 0.6, about 0.7, or about 0.8 cm.sup.3,
including any value and range therebetween.
[0093] Accordingly, in some embodiments, the matrix has a
pre-expansion total surface area ranging from total about 3 to
about 5 cm.sup.2. In some embodiments, the matrix has a
pre-expansion total surface area ranging from total about 3 to
about 5 cm.sup.2. In some embodiments, the matrix has a
pre-expansion total surface area ranging from total about 3.5 to
about 4.5 cm.sup.2. In some embodiments, the matrix has a
pre-expansion total surface area of about 3 cm.sup.2, about 3.1
cm.sup.2, 3.2 cm.sup.2, about 3.3 cm.sup.2, about 3.4 cm.sup.2,
about 3.5 cm.sup.2, 3.6 cm.sup.2, about 3.7 cm.sup.2, 3.8 cm.sup.2,
about 3.9 cm.sup.2, about 4 cm.sup.2, about 4.1 cm.sup.2, 4.2
cm.sup.2, about 4.3 cm.sup.2, 4.4 cm.sup.2, about 4.5 cm.sup.2,
about 4.6 cm.sup.2, about 4.7 cm.sup.2, 4.8 cm.sup.2, about 4.9
cm.sup.2, or about 5 cm.sup.2, including any value and range
therebetween.
[0094] The term "matrix" is used herein interchangeably with the
terms "composition" and "composition-of-matter", and defines a
3-dimentional structure that is formed from e.g., the OC-material.
The matrices described herein may differ in their secondary,
tertiary and quaternary structures from the OC used in their
formation.
[0095] The term "biodegradable" as used in the context of the
present disclosure describes a material which can decompose under
physiological and/or environmental conditions into breakdown
products. Such physiological and/or environmental conditions
include, for example, hydrolysis (decomposition via hydrolytic
cleavage), enzymatic catalysis (enzymatic degradation), and
mechanical interactions. This term typically refers to substances
that decompose under these conditions such that at least 30 weight
percent of the substance decompose within a time period shorter
than one year. The term "biodegradable" as used in the context of
the present disclosure also encompasses the term "bioresorbable",
which describes a substance that decomposes under physiological
conditions to break down to products that undergo bioresorption
into the host-organism, namely, become metabolites of the
biochemical systems of the host-organism.
[0096] The matrix may be in any shape or form, e.g., having a
substantially, polygonal or rectangular (including substantially
square), substantially circular and/or substantially oval
cross-section along at least one axis. For example, the matrix may
have a substantially box-like shape, having a substantially
rectangular cross-section (optionally with rounded corners) along 3
axes; a substantially cylindrical shape, having substantially
circular and/or substantially oval cross-section along one axis,
and a substantially rectangular cross-section (optionally with
rounded corners) along 2 axes; or a substantially spherical or
ovoid shape, having a substantially circular and/or substantially
oval cross-section along 3 axes. Other shapes, forms and sizes of
the disclosed composition may be selected from, without being
limited thereto, plugs, disks, rods, tubes, conical cylinders,
spheres, half and spheres, cubes, rectangles, triangles, or
saucers.
[0097] As used herein, the terms "contact", or "exposure" in the
context of aqueous solution refer to any manner in which a
composition of the present disclosure is brought into a position
where it can at least partially absorb the aqueous solution. The
term "aqueous solution" refers to a solution in which water is the
dissolving medium or solvent. In some embodiments, the aqueous
solution comprises body fluid such as blood. For example,
"contacting" may comprise immersing the composition in a bleeding
site.
[0098] In some embodiments, the composition is in the form of
pellet or tablet, (e.g., optionally as shown in FIGS. 1A-B). In
some embodiments, the composition is in the form of a wound
dressing. The term "wound dressing", as used in the context of the
present disclosure, refers to dressings for topical application
onto/into wound and/or bleeding site. Terms such as "wound
plaster", "wound bandage" or "wound covering" can also be used
synonymously.
[0099] In some embodiments, the matrix has a density of 0.7 to 1.4
gr/cm.sup.3, 0.7 to 1.3 gr/cm.sup.3, 0.8 to 1.2 gr/cm.sup.3, 0.9 to
1.2 gr/cm.sup.3, 1.1 to 1.2 gr/cm.sup.3, 0.8 to 1.3 gr/cm.sup.3,
0.7 to 1.1 gr/cm.sup.3, 0.7 to 1 gr/cm.sup.3, 0.7 to 0.9
gr/cm.sup.3, 0.7 to 0.8 gr/cm.sup.3. In some embodiments, the
matrix has a density of 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, or 1.4
gr/cm.sup.3, including any value and range therebetween. In some
embodiments, the matrix has a density of about 1.2 gr/cm.sup.3.
Herein, by "density", it is meant to refer to the non-expanded
state, i.e. prior to exposure to aqueous solution.
[0100] In some embodiments, the volume of the matrix may be greater
than 1 mm.sup.3. In some embodiments, the volume of the matrix may
be at least 5 mm.sup.3. In some embodiments, the volume of the
matrix may be greater than 10 mm.sup.3. In some embodiments, the
volume of the matrix may be about 5, 10, 15, 20, 25, 30, 35, 40,
45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mm.sup.3,
including any value and range therebetween. In some embodiments,
the volume of the matrix may be greater than 100 mm.sup.3. In some
embodiments, the volume of the matrix may be about 1 to 100, 1 to
10, e.g., about 5 mm.sup.3. Herein, by "volume of the matrix", it
is meant to refer to the non-expanded state, i.e. prior to exposure
to aqueous solution.
[0101] The term "oxidized cellulose" (or "OC") refers to a
cellulose derivative in which at least some of the primary alcohol
groups, e.g., on the carbon 6 of the anhydroglucose unit is
oxidized to a carboxylic acid, and is optionally functionalized. OC
may include materials, products, articles, or compositions
comprising or consisting essentially of OC, e.g., a dressing,
fibrin glue, synthetic glue, pad, matrix, powder, tab, pill,
suture, fiber, stent, implant, scaffold, solution, gel, wax,
gelatin and the like.
[0102] OC may be produced by applying an oxidizing agent on
cellulose. The oxidizing agent may be selected from, without being
limited thereto, chlorine, hydrogen peroxide, peracetic acid,
chlorine dioxide, nitrogen dioxide, persulfates, permanganate,
dichromate-sulfuric acid, hypochlorous acid, hypohalites,
periodates, or any combination thereof, and/or a variety of metal
catalysts. Oxidized cellulose may contain carboxylic acid,
aldehyde, and/or ketone groups, instead of, or in addition to the
original hydroxyl groups of the starting material, cellulose,
depending on the nature of the oxidant and reaction conditions.
[0103] The OC in the compositions of the invention is typically,
but not exclusively, in the form of pellet, capsule, or tablet.
[0104] The term "tablet" is used in its common context, and refers
to a solid composition made by compressing and/or molding a mixture
of compositions in a form convenient for application to any body
cavity. This term includes matrix e.g., pharmaceutical compositions
of all shapes and sizes. The term "pellet" shall herewith include
granules and tablets which can be understood as pellets of various
sizes and shapes.
[0105] In exemplary embodiments, OC has been oxidized to contain
carboxyl moieties in amounts effective to provide biodegradability.
For example, U.S. Pat. No. 3,364,200 discloses the preparation of
carboxylic-oxidized cellulose with an oxidizing agent such as
dinitrogen tetroxide in a Freon medium. U.S. Pat. No. 5,180,398
discloses the preparation of carboxylic-oxidized cellulose with an
oxidizing agent such as nitrogen dioxide in a per-fluorocarbon
solvent. After oxidation by either method, the fabric may be
thoroughly washed with a solvent such as carbon tetrachloride,
followed by aqueous solution of 50 percent isopropyl alcohol (IPA),
and finally with 99% IPA. Prior to oxidation, the fabric can be
constructed in the desired woven or nonwoven construct.
[0106] Typically, hemostats that are compatible with acid-sensitive
species comprise e.g., fabric substrates prepared from a
biocompatible, aldehyde-oxidized polysaccharide. In such exemplary
hemostats, the polysaccharide contains an amount of aldehyde
moieties effective to render the modified polysaccharide
biodegradable, meaning that the polysaccharide is degradable by the
body into components that are either resorbable by the body, or
that can be passed readily by the body. More particularly, the
biodegraded components do not elicit permanent chronic foreign body
reaction when they are absorbed by the body, such that
substantially no permanent trace or residual of the component is
retained at the implantation site.
[0107] In certain embodiments of the present disclosure, the OC
comprises layers prepared from biocompatible, biodegradable,
aldehyde-oxidized regenerated cellulose. In some embodiments, the
OC comprises or consists essentially of oxidized regenerated
cellulose (ORC) e.g., aldehyde-oxidized regenerated cellulose. In
some embodiments, the aldehyde-oxidized regenerated cellulose is
one comprising repeating units of Structure II in U.S. Pat. No.
8,709,463. In some embodiments, ORC is used to prepare hemostats.
Typically, regenerated cellulose is preferred due to its higher
degree of uniformity versus cellulose that has not been
regenerated. Exemplary regenerated cellulose and a detailed
description of how to make ORC is set forth in U.S. Pat. No.
3,364,200 and U.S. Pat. No. 5,180,398.
[0108] As indicated above, in some embodiments, the degree of
oxidation of the OC may be important to its functional properties
such as biocompatibility and bioabsorbability. Products including
various degrees of OC oxidation exist, such as a surgical hemostat
in which carboxylic acid groups are present at a concentration of
18 to 21% by weight of the oxidized cellulose.
[0109] As used herein with reference to OC, the terms "oxidation
level", "degree of oxidation", "carboxyl content", and
"carboxylation level" are interchangeable, and may be determined
per United States Pharmacopeia (USP) 23-NF18.
[0110] Accordingly, in some embodiments, the carboxyl content of
the OC is 12 to 24%, by weight. In some embodiments, the carboxyl
content of the OC is 12 to 23%, by weight. In some embodiments, the
carboxyl content of the OC is 12 to 22%, by weight. In some
embodiments, the carboxyl content of the OC is 12 to 21%, by
weight.
[0111] In some embodiments, the carboxyl content of the OC is 16 to
24%, by weight and the composition can function as a hemostat. In
some embodiments, the carboxyl content of the OC is 17 to 23%, by
weight. In some embodiments, the carboxyl content of the OC is 18
to 22%, by weight. In some embodiments, the carboxyl content of the
OC is 18 to 21%, by weight.
[0112] In some embodiments, the carboxyl content of the OC is 12 to
18%, by weight. In some embodiments, the carboxyl content of the OC
is 12 to 17%, by weight. In some embodiments, the carboxyl content
of the OC is 12 to 16%, by weight.
[0113] In some embodiments, the carboxyl content of the OC is 12%,
13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, or 24%, by
weight, including any value and range therebetween.
[0114] It is appreciated that while the usual source for OC is
plant material, OC may also be derived from a bacterial source. In
some embodiments, the OC is derived from a plant source.
[0115] In some embodiments, the cellulose for use with the present
invention does not include CMC.
[0116] According to some embodiments, the matrix comprises fibers
prepared from a biocompatible polymer(s) and comprises a surface
that possesses properties suitable for use as a hemostat, e.g.,
strength, flexibility and porosity.
[0117] In certain embodiments of the invention, the OC (e.g., ORC)
may be further combined with a hemostatic agent, or other
biological or therapeutic compounds, moieties or species, including
drugs and pharmaceutical agents. In some embodiments, to improve
the hemostatic performance, scaffolds based on the above materials
can be combined with biologically-derived clotting factors, such as
thrombin and fibrinogen. In yet another embodiment, the disclosed
ORC-based composition may be combined with an additive, such as
carboxymethyl cellulose (CMC), calcium salt, anti-infective agent,
hemostasis promoting agent, gelatin, collagen, saline, or any
combination thereof.
[0118] In further embodiments of the present invention, the
disclosed ORC-based composition may be combined with various
additives to further improve the hemostatic properties, wound
healing properties, and handling properties. Utilizing additives
known to those skilled in the art includes for example: hemostatic
additives such as gelatin, collagen, cellulose, chitosan,
polysaccharides, starch; biologics-based hemostatic agents as
exemplified by thrombin, fibrinogen, and fibrin. Additional
biologics hemostatic agents include, without limitation,
procoagulant enzymes, proteins, and peptides. Each such agent can
be naturally occurring, recombinant, or synthetic, and may be
further selected from: fibronectin, heparinase, Factor X/Xa, Factor
VII/VIIa, Factor IX/IXa, Factor XI/XIa, Factor XII/XIIa, tissue
factor, batroxobin, ancrod, ecarin, von Willebrand Factor, albumin,
platelet surface glycoproteins, vasopressin and vasopressin
analogs, epinephrine, selectin, procoagulant venom, plasminogen
activator inhibitor, platelet activating agents, synthetic peptides
having hemostatic activity, derivatives of the above, and any
combination thereof anti-infective agents, such as chlorhexidine
gluconate (CHG), triclosan, silver, and similar
anti-bacterial/microbial agents that are known in the art;
additives that increase the stickiness of the hemostat; and other
additives known in the art.
[0119] In some embodiments, the OC, such as ORC, is provided in the
form of a pellet (compressed or non-compressed), a bead, a granule,
an aggregate, a fiber(s), sheets (including a woven, nonwoven,
knitted, milled or fine fiber and combinations thereof), all either
independently used or dispersed in a pharmaceutically acceptable
vehicle or in other forms.
[0120] Non-limiting examples for OC-based material that are either
in pellet form, or may be ground to first obtain a plurality of
sheets and may be utilized, include different textured OC or ORC
material, for example, and without being limited thereto,
INTERCEED.RTM. absorbable adhesion barrier, SURGICEL.RTM. Original
absorbable hemostat (loose knit of ORC), SURGICEL.RTM. NU-KNIT.RTM.
absorbable hemostat (densely woven knit of ORC), SURGICEL.RTM.
FIBRILLAR.TM. absorbable hemostat (soft, lightweight, layered ORC),
SURGICEL.RTM. SNoW.TM. absorbable hemostat (structured non-woven
fabric, needle punched with interlocking fibers) and SURGICEL.RTM.
Powder absorbable hemostat, or GelitaCel.RTM. resorbable cellulose
surgical dressing from Gelita Medical BV, Amsterdam, The
Netherlands.
[0121] SURGICEL.RTM. Powder absorbable hemostat is a powder that
comprises aggregate of small ORC fiber fragments that may spread
across a large surface area and form a durable clot that will not
be washed away or rebleed when irrigated.
[0122] Typically, woven fabric is composed of two sets of yarns.
One set of yarns, the warp, runs along the length of the fabric.
The other set of yarns, the fill or weft, is perpendicular to the
warp. Woven fabrics are held together by weaving the warp and the
fill yarns over and under each other.
[0123] "Non-woven fabric" refers to a fabric-like material made
from long fibers, bonded together by chemical, mechanical, heat or
solvent treatment. The term is used in the textile manufacturing
industry to denote fabrics, such as felt, which are neither woven
nor knitted. Thus, the phrase "non-woven" refers to a sheet, web or
mat of directionally or randomly oriented fibers, where fibers are
not intercalated but rather bonded through various means, including
e.g., friction, cohesion and/or adhesion. The term "non-woven
fabric" also includes, but is not limited to, bonded fabrics,
formed fabrics, or engineered fabrics, that are manufactured by
processes other than spinning, weaving or knitting.
[0124] Typically, but not exclusively, the term "non-woven fabric"
also relates to a porous, textile-like material, composed primarily
or entirely of staple fibers assembled in a web, sheet or batt,
usually in flat sheet form. The structure of the non-woven fabric
is based on the arrangement of, for example, staple fibers that are
typically arranged more or less randomly. The tensile,
stress-strain and tactile properties of the non-woven fabric
ordinarily stem from fiber to fiber friction created by
entanglement and reinforcement of, for example, staple fibers,
and/or from adhesive, chemical or physical bonding.
Notwithstanding, the raw materials used to manufacture the
non-woven fabric may be yarns, scrims, netting, or filaments made
by processes that include spinning, weaving or knitting (as
described e.g., in Patent Application having the Publication
number: EP1802358A2).
[0125] Typically, knitted fabrics are made from only one set of
yarns, all running in the same direction. Some knits have their
yarns running along the length of the fabric, while others have
their yarns running across the width of the fabric. Knit fabrics
may be held together by looping the yarns around each other.
Knitting creates ridges in the resulting fabric.
[0126] As shown in the Examples section below, the ORC originated
from short fibers ("ORC Short") expanded up to approximately 5
times its original volume, while ORC made of long fibers ORC ("ORC
Long") expanded up to 3 times its original volume. Increasing the
compression pressure to 2 or 5 tons did not have a beneficial
effect on the expansion factor. The non-woven fabrics exhibited a
superior overall expansion effect. Typical size distribution of ORC
fiber types, "ORC Long" or "ORC Short" is as described in the
Examples section below (Table 1).
[0127] In some embodiments, the above-mentioned forms (e.g.,
non-woven, knitted, etc.) of the OC-based materials, does not
necessarily remain the same in the compressed form of the disclosed
matrix.
[0128] The fabricated compressed ORC materials A, B, C and D (as
described in the Examples section below) all exhibited superior
expansion factors to the milled powders.
[0129] The compositions of the invention are non-aqueous
compositions, which means that the main liquid in the compositions
is not water and the compositions have very low water content or no
water at all prior to their immersion in an aqueous environment.
Thus, in some embodiments, the water content of the composition is
lower than 10% (w/w). In some embodiments, the water content of the
composition is lower than 8% (w/w). In some embodiments, the total
water content of the composition is lower than 5%, 4%, 3%, 2%, or
1% (w/w). In some embodiments, the composition does not contain
water. In some embodiments, the composition does not comprise any
solvent.
[0130] In some embodiments, the matrix further comprises a
pharmaceutically acceptable excipient or additive. Excipients and
additives may include any pharmaceutically suitable excipient, such
as, without being limited thereto, calcium salt, human albumin,
mannitol, sodium acetate, sodium chloride, sodium citrate
dihydrate, gluconate buffer, saccharose, glycine, sodium acetate,
histidine, and polyethylene glycol (PEG).
[0131] Calcium salt used with the invention may be in the form of
calcium chloride salt. Alternatively, additional salts may be used,
such as calcium acetate and/or calcium citrate.
[0132] In some embodiments, the composition may further comprise a
biologically active agent. Non-limiting biologically active agents
that may be included in the composition include therapeutic agents
such as antibiotics, anti-inflammatory agents, growth factors, or
clotting factors as described above. For example, the composition
may further comprise fibrinogen or thrombin.
[0133] As used herein, "thrombin" denotes an activated enzyme which
results from the proteolytic cleavage of prothrombin (factor II).
Thrombin may be produced by a variety of methods of production
known in the art, and includes, but is not limited to, recombinant
thrombin and plasma derived thrombin.
[0134] Human thrombin is a 295 amino acid protein composed of two
polypeptide chains joined by a disulfide bond. Both human and
non-human (e.g., bovine) thrombin may be used within the scope of
the present disclosure.
[0135] The term "fibrinogen" without more is intended to include
any type of fibrinogen such as, without limitation fibrinogen in a
cryoprecipitate. Fibrinogen, therefore, refers to monomeric and
dimeric fibrinogen molecules having the monomer structure
(A.alpha.B.beta..gamma.), hybrid molecules, and variants thereof,
whether naturally occurring, modified, or synthetic. The term
"fibrinogen" refers generally to fibrinogen from humans, but may
include fibrinogen of any species, especially mammalian
species.
[0136] Any preparation for therapeutic use must be sterile.
Especially when handling blood products, the sterility issue is
crucial, and specifically the issue of viral inactivation. In
general, viral inactivation may be carried out by any method,
including solvent detergent, heat inactivation, irradiation, and
nanofiltration. Typically, the standard for viral inactivation
requires using two different methods. Additionally, the U.S. Food
and Drug Administration (FDA) standard for sterility requires
filtration.
[0137] In another embodiment, the disclosed composition may be used
in conjunction with a backing, pad, scaffold, or matrix to provide
mechanical strength to cover the wound surface. In this case, the
instant matrix is supported on a pad for ease of application or
tamponade.
[0138] In some embodiments, the matrix is characterized by an
antimicrobial effectiveness. In some embodiments, the matrix is for
antimicrobial use e.g., in inhibiting or reducing the formation of
load of a microorganism. As used herein, the term "antimicrobial"
is intended to include destroying or inhibiting the growth of
microorganisms such as pathogenic bacteria. The antibacterial
effectiveness, and in some embodiments, may be for use in
inhibiting or reducing the formation of load of a
microorganism.
[0139] It is appreciated that the composition may be applied, for
example, by sticking the composition directly onto the bleeding
site. Accordingly, the composition does not need to be further
spread on or applied to a solid surface, object, or other solid
medium such as a strip or a film in order to be in the appropriate
form for applying to the bleeding site. Nevertheless, a suitable
applicator may be used in order to apply, locate, spread or stick
the composition onto the bleeding site, for the purpose of easy
access and handling.
[0140] As provided herein, the OC matrix may be used as an
immediate hemostat without the need for time consuming and
cumbersome manual compression at the wound site. Through the
compression exerted by expansion of the material itself in the
wound site, following absorption with blood, the compressed
material can stop or reduce the bleeding without further external
compression.
[0141] In an aspect of the present invention, there is provided a
method of treating a wound comprising the step of applying (e.g.,
contacting) the disclosed biodegradable hemostatic matrix in any
embodiment thereof onto and/or into the wound of a subject in a
need thereof.
[0142] By "treating a wound" it further meant to encompass reducing
blood loss at a bleeding site of a tissue, e.g., in a patient
undergoing surgery. Accordingly, in some embodiments, the method is
for reducing blood loss at a bleeding site of a tissue, e.g., in a
patient undergoing surgery, comprises contacting the disclosed
composition in an embodiment thereof with the bleeding site.
[0143] Reference is now made to FIG. 2, demonstrating the ability
of the composition of the invention to expand upon exposing to body
fluid, while taking on the shape of the wound site.
[0144] As used herein, the term "subject" shall mean any animal
including, without limitation, a human, a mouse, a rat, a rabbit, a
non-human primate, or any other mammal. In some embodiments, the
subject is human, e.g., a human patient. The subject may be male or
female.
[0145] Accordingly, the disclosed matrix in any embodiment thereof,
is for use in controlling bleeding in a soft tissue of a subject in
a need thereof. The term "soft tissues" as used herein relates to
body tissue that is not hardened or calcified. This term especially
relates to soft tissues that are vascularized and therefore may be
a source of bleeding. Examples for such tissues include but are not
limited to connective tissue (such as tendons, ligaments, fascia,
skin, fibrous tissues, fat, and synovial membranes), muscles, and
internal organs. In general, soft tissues are meant to exclude bone
tissue.
[0146] In some embodiments, the composition is homogeneous. As used
herein, by "homogeneous" it is meant to refer to a uniform
composition and texture throughout, i.e. having a density that
varies within less than .+-.20%, less than .+-.15%, less than
.+-.10%, less than .+-.5%, less than .+-.2%, or less than
.+-.1%.
[0147] A desired combination of properties of the disclosed matrix,
e.g., having a density ranging from 0.8 to 1.2 gr/cm.sup.3, and
being expandable to at least 3 times its original volume within 4
sec upon contact with an aqueous solution, was found to be
achievable e.g., by compressing the OC material e.g., non-woven
material ORC source.
[0148] Accordingly, there is provided a method of making the
disclosed hemostatic matrix according to any embodiment thereof,
the method comprising the step of compressing or compacting an
OC-based material by applying on a surface thereof a pressure
ranging from about 0.2 to about 7 ton/per cm.sup.2. In some
embodiments, the method comprises the step of compressing or
compacting an OC-based material by applying on one or more surfaces
thereof a pressure ranging from 0.3 to 3.5 ton/per cm.sup.2. In
some embodiments, the method comprises the step of compressing or
compacting an OC-based material by applying on a surface thereof a
pressure of 0.2, 0.3, 0.4, 0.5, 0.5, 0.7, 0.8, 0.9, 1, 1.1, 1.2,
1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,
2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4,
4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4,
5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,
6.9, or 7 ton/per cm.sup.2, including any value and range
therebetween.
[0149] In another aspect of the present disclosure, there is
provided a matrix produced by the method of compressing an OC-based
material by applying on a surface thereof a pressure indicated
herein. In some embodiments, the compression is applied by applying
a pressure e.g., using a hydraulic press. In some embodiments, the
pressure applied ranges from about 0.2 to about 7 ton/per cm.sup.2,
0.3 to 3 ton, or 0.5 to 2 ton per 1 cm.sup.2, e.g., 0.2, 0.3, 0.4,
0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,
1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2,
3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3, 4, 4.1, 4.2, 4.3, 4.4, 4.5,
4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9,
6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7 ton per 1
cm.sup.2, including any value and range therebetween.
[0150] In some embodiments of the method, the OC material comprises
ORC. In some embodiments of this method, the ORC is in the
non-woven form. In some embodiments, the method further comprises
the step of mixing the OC material with one or more additives
selected from, without being limited thereto, calcium salt,
anti-infective agent, and hemostasis promoting agent.
[0151] As used herein the term "about" refers to .+-.10%.
[0152] The terms "comprises", "comprising", "includes",
"including", "contains", "containing", "has", "having", and their
conjugates mean "including but not limited to". The term
"consisting of" means "including and limited to". The term
"consisting essentially of" means that the composition, method or
structure may include additional ingredients, steps and/or parts,
but only if the additional ingredients, steps and/or parts do not
materially alter the basic and novel characteristics of the claimed
composition, method or structure.
[0153] The word "exemplary" is used herein to mean "serving as an
example, instance or illustration". Any embodiment described as
"exemplary" is not necessarily to be construed as preferred or
advantageous over other embodiments and/or to exclude the
incorporation of features from other embodiments.
[0154] The word "optionally" is used herein to mean "is provided in
some embodiments and not provided in other embodiments". Any
particular embodiment of the invention may include a plurality of
"optional" features unless such features conflict.
[0155] As used herein, the singular form "a", "an", and "the"
include plural references unless the context clearly dictates
otherwise. For example, the term "a compound" or "at least one
compound" may include a plurality of compounds, including mixtures
thereof.
[0156] Throughout this application, various embodiments of this
invention may be presented in a range format. It should be
understood that the description in range format is merely for
convenience and brevity and should not be construed as an
inflexible limitation on the scope of the invention. Accordingly,
the description of a range should be considered to have
specifically disclosed all the possible subranges as well as
individual numerical values within that range. For example,
description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1
to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as
well as individual numbers within that range, for example, 1, 2, 3,
4, 5, and 6. This applies regardless of the breadth of the
range.
[0157] Whenever a numerical range is indicated herein, it is meant
to include any cited numeral (fractional or integral) within the
indicated range. The phrases "ranging/ranges between" a first
indicate number and a second indicate number and "ranging/ranges
from" a first indicate number "to" a second indicate number are
used herein interchangeably and are meant to include the first and
second indicated numbers and all the fractional and integral
numerals therebetween.
[0158] As used herein the term "method" refers to manners, means,
techniques and procedures for accomplishing a given task including,
but not limited to, those manners, means, techniques and procedures
either known to, or readily developed from known manners, means,
techniques and procedures by practitioners of the chemical,
pharmacological, biological, biochemical and medical arts.
[0159] As used herein, the term "treating" includes abrogating,
substantially inhibiting, slowing or reversing the progression of a
condition, substantially ameliorating clinical or aesthetical
symptoms of a condition or substantially preventing the appearance
of clinical or aesthetical symptoms of a condition.
[0160] As used herein, and unless stated otherwise, the terms "by
weight", "w/w", "weight percent", or "wt. %", which are used herein
interchangeably describe the concentration of a particular
substance out of the total weight of the corresponding mixture,
solution, formulation or composition.
[0161] As used herein, the term "bleeding" refers to extravasation
of blood from any component of the circulatory system. A "bleeding"
thus encompasses unwanted, uncontrolled and often excessive
bleeding in connection with surgery, trauma, or other forms of
tissue damage, as well as unwanted bleedings in patients having
bleeding disorders.
[0162] As used herein, the terms "controlling" "preventing" or
"reducing", which may be used herein interchangeably in the context
of the bleeding, including any grammatical inflection thereof,
indicate that the rate of the blood extravagated is essentially
nullified or is reduced by at least 10%, at least 20%, at least
30%, at least 40%, at least 50%, at least 60%, at least 70%, at
least 80%, at least 90%, or even by 100%, of the initial rate of
bleeding, compared to situation lacking the contact of the
disclosed composition in/on the bleeding site. Methods for
determining a level of appearance of bleeding are known in the
art.
[0163] Further, in some embodiments, the terms "controlling",
"preventing", or "reducing", in the context of the bleeding are
also meant to encompass at least partially sealing blood vessels at
the bleeding site either in soft tissues.
[0164] In those instances where a convention analogous to "at least
one of A, B, and C, etc." is used, in general such a construction
is intended in the sense one having skill in the art would
understand the convention (e.g., "a composition having at least one
of A, B, and C" would include but not be limited to compositions
that have A alone, B alone, C alone, A and B together, A and C
together, B and C together, and/or A, B, and C together, etc.). It
will be further understood by those within the art that virtually
any disjunctive word and/or phrase presenting two or more
alternative terms, whether in the description, claims, or drawings,
should be understood to contemplate the possibilities of including
one of the terms, either of the terms, or both terms. For example,
the phrase "A or B" will be understood to include the possibilities
of "A", "B", or "A and B".
[0165] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable subcombination
or as suitable in any other described embodiment of the invention.
Certain features described in the context of various embodiments
are not to be considered essential features of those embodiments,
unless the embodiment is inoperative without those elements.
[0166] Various embodiments and aspects of the present invention as
delineated hereinabove and as claimed in the claims section below
find experimental support in the following examples.
EXAMPLES
[0167] Reference is now made to the following examples, which
together with the above descriptions illustrate some embodiments of
the invention in a non-limiting fashion.
[0168] Materials and Methods
[0169] Materials
[0170] Table 1 below presents ORC form used for exemplary expansion
experiments.
TABLE-US-00001 TABLE 1 Material Form* ORC tablet A Knitted fabric
ORC tablet B Knitted fabric ORC tablet C Non-woven fabric ORC
tablet D Non-woven fabric "ORC short" milled ORC powder containing
particles with size distribution of D90 less than 177 .mu.m and D50
less than 95 .mu.m "ORC Long" milled ORC powder containing
particles with size distribution of D90 less than 350 .mu.m and D50
is less than 167 .mu.m *Tablets "A" and "B" are made from a Knitted
fabric (A = SURGICEL original; B = NU-KNIT); Tablets "C" and "D"
are made from either a woven, or non-woven (non-knitted) material
(C = FIBRILLAR; D = SNoW).
[0171] In additional exemplary procedures, the following ORC
materials: SURGICEL, NU-KNIT, FIBRILLAR, SNoW, and Milled ORC were
further tested as described below.
[0172] Sample Preparation
[0173] Samples of 0.5 g were weighed from each material. Weighed
samples were pressed into a circular 1 cm diameter tablet mold.
0.5, 2, and 5 tons compression force was administered resulting in
ORC tablets which varying in their compression levels.
[0174] Weighed samples were placed within a round pellet die mold
having a 1 cm diameter. In exemplary procedures, the mold used was
a metallic cylinder having a 1 cm diameter. A metallic rod having a
similar diameter to the mold opening was inserted into the mold and
placed on top of the sample material. Force was used on the rod in
order to compress the sample while the rod continues to be inserted
into the mold containing the sample. The force was applied by the
rod is in the vertical axis of the cylindrical mold. The force was
applied by a manual hydraulic press until reaching a predetermined
force such as 0.5, 2, and 5 tons compression force. Once achieved,
the rod was removed, and the resulting tablets were removed from
the mold.
[0175] Methods
[0176] The thickness of each pressed sample was measured using
calipers to calculate its initial volume. A clear graduated 12 mm
diameter cylinder was filled up to 10 mL with saline. Next, the 10
mm diameter sample tablet was released into the saline in the
graduated cylinder from the top face of the cylinder. At the
point-of-release a timer was started. The samples, mostly
constrained horizontally, began to absorb the liquid and expand
predominantly in the vertical axis. The volume of the expending
sample was visualized and evaluated when appropriate through the
clear graduated cylinder. Expansion factor was evaluated at 4
seconds after point-of-release. The maximal expansion factor as
well as the length of time until maximum expansion was achieved,
were documented.
[0177] Instruments: [0178] 1. Caliper--Sylva `SCal pro IP67` [0179]
2. Graduated 12 mm diameter cylinder--`Plasti Brand` [0180] 3.
Manual Hydraulic Press--Specac Atlas series 15-ton press [0181] 4.
10 mm Evacuable Pellet Die--Specac [0182] 5. Digital Timer
TM-44--MICROTEMP ELECTRICS CO., LTD
Example 1
Degree of Expansion
[0183] In exemplary procedures, the speed and degree of expansion
of expandable tablets produced, inter alia, from different textured
ORC material were assessed. The results provide an estimate as to
the potential of each type of compressed ORC to function as an
efficacious hemostat in various blood loss scenarios.
[0184] Expansion Factor: The degree of expansion (Expansion factor)
is defined as the multiple of the original volume (mL) at maximum
expansion. For example, if the original volume of a tablet was 2
cm.sup.3, and the maximum expansion volume was 8 cm.sup.3, the
expansion factor would be 4.
[0185] Time to maximum expansion: The amount of time from the
tablet's exposure to saline until their full expansion was
measured. Time was measured up to 300 seconds.
[0186] Results are summarized in Tables 2A and 2B showing the
expansion factor and time to expansion of ORC tablets (fixed to 4
sec in Table 2B) exposed to saline, and are further illustrated in
FIGS. 3A and 3B.
TABLE-US-00002 TABLE 2A Pressure Maximal* Time to (Ton per
Expansion expansion Composition 0.785 cm.sup.2) (mL) (sec) 0.5 1.86
65 ORC Short 2 1.10 300 tablet 5 1.02 300 ORC Long 0.5 1.36 10
tablet 2 1.34 300 5 1.08 300 ORC 0.5 3.12 10 tablet B 2 2.28 30 5
2.68 35 ORC 0.5 2.58 5 tablet A 2 2.23 8 5 2.19 8 ORC 0.5 7.32 5
tablet D 2 7.66 5 5 7.92 6 ORC 0.5 6.57 3 tablet C 2 7.66 8 5 7.22
16 *The initial volume was similar for all the samples
[0187] The samples of the milled ORC "ORC Short" and "ORC Long"
exhibited the least expansion volume. Moreover, when exposed to
saline the fibers dissolve to a certain extent and immediately
begin to break down. When compressed under 0.5-ton (per 0.785
cm.sup.2) pressure, the "ORC short" expanded up to approximately 5
times its original volume, while "ORC Long" expanded up to 3 times
its original volume. Increasing the compression pressure to 2 or 5
tons did not have a beneficial effect on the expansion factor.
However, increasing the compression strength hindered the tablets
capability to expand resulting in time to max expansion that
surpassed the 5-minute time limit defined for the assay.
[0188] The fabricated compressed material A, B, C and D all
exhibited superior expansion factors to the milled powders.
[0189] Of the knitted fabrics (materials A and B)--material B
exhibited slightly better expansion properties than material A,
with no apparent effect of increased pressure on expansion degree.
However, the time required for the maximum expansion was
significantly shorter in material A, compared to material B in all
compression strengths (5-8 sec; 10-35 sec). In both fabrics--like
in the powdered ORC--a 0.5 ton compressed tablet expanded faster
than the more compressed tablets.
[0190] A 0.5-ton compression reduced the expansion factor for both
fabrics. Time to maximal expansion was very fast in the material D
tablet (5 sec) for all the compression pressures. Material C
tablets exhibited direct effect of compression on "time to max
expansion" in which increased tablet pressure directly increased
the time to expansion from 3 sec (0.5 ton) to 16 sec (5 tons).
Materials A and C reached their maximal expansion at the same time
(8 sec at 2-ton compression) (see FIG. 3B). The 2-ton compression
was chosen given its combined results in expansion volume and time
of expansion (as shown FIGS. 3A and 3B).
[0191] The results presented in Table 2B which are further
illustrated in FIGS. 4A-5 demonstrate that an ORC density of about
0.8 to 1.2 gr/cm.sup.3, and particularly, 0.95 to 1.2 gr/cm.sup.3
provides optimal expansion after 4 sec, with the "FIBRILLAR" and
"SNoW" exhibiting the highest expansion factor. For comparison,
Gauze Pad (non-oxidized cellulose) was also tested, showing poorer
expansion factors for certain density values compared to oxidized
cellulose samples.
TABLE-US-00003 TABLE 2B Disc Pressure Disc Disc Disc surface Disc
Expansion Max (ton) per Weight Height (h) Diameter area Volume
Density Factor Expansion Mater. 0.785 cm.sup.2* (g) (cm) (cm)
(cm.sup.2)** (cm.sup.3) (gr/cm.sup.3) at 4 sec Factor 1 0.5 0.5182
0.9215 1.0494 4.7653 0.7966 0.651 3.06 3.06 1 0.5160 0.7042 1.0421
4.0093 0.6003 0.860 3.45 3.45 1.5 0.5123 0.5763 1.0195 3.4767
0.4702 1.089 3.55 4.25 2 0.5139 0.5373 1.0147 3.3287 0.4343 1.183
4.59 4.90 5 0.5173 0.5125 1.0098 3.2259 0.4102 1.260 3.33 5.44 2
0.5 0.5135 0.6485 1.0207 3.7142 0.5304 0.969 4.72 4.97 1 0.5145
0.6258 1.0276 3.6772 0.5188 0.993 4.31 4.96 1.5 0.5083 0.5446
1.0142 3.3494 0.4398 1.156 4.55 5.38 2 0.5104 0.5358 1.0075 3.2886
0.4269 1.195 4.83 6.45 5 0.5084 0.5158 1.0101 3.2380 0.4132 1.230
3.71 6.93 3 0.5 0.5062 0.6922 1.0198 3.8490 0.5650 0.898 4.99 6.04
1 0.5164 0.6463 1.0169 3.6873 0.5247 0.984 6.10 6.54 1.5 0.5040
0.5718 1.0145 3.4371 0.4619 1.091 5.77 6.05 2 0.5072 0.5396 1.0104
3.3147 0.4324 1.173 5.85 6.86 5 0.5105 0.5081 1.0059 3.1933 0.4036
1.264 5.37 8.42 4 0.5 0.5249 0.8909 1.0278 4.5336 0.7388 0.711 4.24
4.51 1 0.5562 0.6527 1.0136 3.6901 0.5263 1.056 6.71 7.15 1.5
0.5365 0.5712 1.0079 3.4025 0.4555 1.177 7.16 7.76 2 0.5221 0.5727
1.0110 3.4228 0.4595 1.136 6.96 7.32 5 0.5277 0.5341 1.0081 3.2865
0.4261 1.238 5.79 7.74 5 0.25 0.4903 0.5552 1.0076 3.3506 0.4425
1.107 2.79 3.84 0.5 0.4826 0.5100 1.0063 3.2013 0.4054 1.190 1.00
2.63 6 0.5 0.5039 0.6038 1.0098 3.515 0.484 1.042 4.07 4.41 1
0.5015 0.5412 1.0064 3.300 0.431 1.165 3.48 4.19 1.5 0.4999 0.5119
1.0040 3.194 0.405 1.234 3.45 4.28 2 0.5101 0.5072 1.0039 3.182
0.401 1.271 3.32 4.23 5 0.5072 0.4847 1.0035 3.111 0.383 1.323 2.70
4.00 *Assuming a round 1 cm mold, and the calculation according to
.pi.r.sup.2 gives 0.785 cm.sup.2. **Surface area of a cylinder =
2.pi.r.sup.2 + 2.pi.rh Materials: "1" - SURGICEL; "2"- NU-KNIT;
"3"- FIBRILLAR; "4" - SNoW; "5" Milled ORC; "6"- Gauze Pad
(non-oxidized cellulose)
[0192] FIG. 6 is also based on Table 2B presenting a graph showing
the ORC materials density vs. the maximal expansion volume (mL) in
saline.
Example 2
In Vivo Study: Porcine Splenic Biopsy Punch Model
[0193] For the in-vivo study, the difference hemostatic efficacy of
representative tablets composed from the different fabrics (knitted
and non-woven) was studied.
[0194] For this study a similar expansion time is recommended.
Therefore, from the knitted materials material A (see Table 2A) was
chosen and from the non-woven materials material C (see Table 2A)
was chosen. As described above, both reached their maximum
expansion at the same time (8 sec at 2-ton compression) (see FIG.
3B). The 2-ton compression was chosen given its combined results in
expansion volume and time of expansion (see FIGS. 3A and 3B).
[0195] Materials
[0196] ORC material C or ORC material A (5 g of each) compressed
into a 0.4 mL (cm.sup.3) tablet by applying a 2-ton compression
force.
[0197] Methods
[0198] Porcine Splenic Biopsy Punch model: A mature, about 60 kg,
female porcine was put on a fast for 24 hours prior to the surgical
procedure. The animal was anesthetized with 1150-1400 mg Ketamine,
115-140 mg Xylazine, 7.5 mg Midazolam. Anesthesia was maintained
with Isoflurane and the abdomen was opened to reveal the
spleen.
[0199] Mean arterial blood pressure, body temperature and heart
rate were continuously monitored throughout the surgical procedure.
The experiment was terminated when mean arterial blood pressure
dropped below 60 mmHg.
[0200] An 8 mm diameter.times.3 mm depth biopsy punch was carried
out on the spleen and the specimen was excised with surgical
scissors. The punch site was allowed to bleed for 30 seconds and
bleeding intensity was visually assessed on a scale of 0-5 (as
described in FIG. 7); "no bleeding" was given a score of 0 and
"intensive bleeding" was given a score of 5. Next, the punch site
was wiped with clean gauze to remove excess blood and a single
tablet was inserted into the puncture wound. Thereafter, the
bleeding rate was re-evaluated according to the scheme describes in
FIG. 7.
[0201] The results are summarized in Table 3 below showing the
effect of ORC tablet application on bleeding levels in an 8 mm
diameter.times.3 mm depth spleen biopsy punch model.
TABLE-US-00004 TABLE 3 Post Pre-treatment treatment bleeding
bleeding Tablet level level .DELTA. bleeding (0.4 cm.sup.3, 2T)
(Spleen) (Spleen) reduction ORC material A 3 1 2 Non-compressed 4 2
2 ORC material C ORC material C 4 1 3
[0202] Application of tablet of ORC material A to a puncture with a
graded bleeding level of 3 ("mild" bleeding) resulted in bleeding
reduction to a grade 1 level ("ooze"). Application of the ORC
material C tablet exhibited superior efficacy and was able to
reduce a 4-grade bleeding level ("moderate" bleeding) down to 1
("ooze"). During application it was shown that the ORC material C
tablet expanded much more rapidly and was able to reduce the
bleeding at higher efficacy and at a faster rate than the tablet of
ORC material A. These results show that the textured of the
properties of the non-woven compressed fabric that expand to
greater volume and at a faster rate than the compressed knitted
ORC, also exhibits improved efficacy in hemostasis of puncture
bleeding. Application of a non-compressed ORC material C exhibited
reduced efficacy--decrease of bleeding level from 4 ("moderate") to
2 ("mild")--suggesting an advantage of the compressed tablet in
immediate hemostasis of puncture wounds over the non-compressed
material.
Example 3
In Vivo Study: Heparinized Porcine Splenic Biopsy Punch Model
[0203] A mature, about 60 kg, female porcine was treated as
described above, with abdomen being opened to reveal the liver or
spleen, and with 27,000 IU of Heparin being administered prior to
biopsy procedure. ACT (Activated Clotting Time) test was used in
order to monitor the Heparin treatment. Accordingly, Heparin boosts
were given in order to maintain stable ACT levels. Heparin is used
as an injectable anticoagulant (through antithrombin III
activation) and therefore this model represents a challenging
bleeding model.
[0204] The liver was subjected to 8 mm diameter.times.3 mm depth
biopsy punch. The Porcine spleen was subjected to 6 mm
diameter.times.3 mm depth biopsy punch. In both organs, the
specimen was excised with surgical scissors. The punch site was
allowed to bleed for 30 seconds and bleeding intensity (level) was
visually assessed on a scale of 0-5, as described above. The
results are summarized in Table 4 showing the effect of ORC tablet
application on bleeding levels in an 8 mm diameter.times.3 mm depth
liver biopsy punch model, and in Table 5 showing the effect of ORC
tablet application on the bleeding level in a 6 mm diameter.times.3
mm depth spleen biopsy punch model. The hemostatic efficacy
evaluation was performed in the porcine liver and in the porcine
spleen. The ORC tablets were manually applied to the wound
sites.
TABLE-US-00005 TABLE 4 Post Pre-Treatment Treatment Bleeding
Bleeding Tablet Level Level .DELTA. bleeding (0.4 cm.sup.3, 2T)
(Liver) (Liver) reduction ORC material C 4 0 4 (Fibrillar)* ORC
material D 4 0 4 (SNoW) ORC short 4 4 0 (milled ORC)
*Triplicate
TABLE-US-00006 TABLE 5 Post Pre-Treatment Treatment Bleeding
Bleeding Tablet Level Level .DELTA. Bleeding (0.4 cm.sup.3, 2T)
(Spleen) (Spleen) Reduction ORC material C 3 0 3 ORC material D 2 0
2 ORC material D 4 0 4 ORC short 3 2 1 ORC short 4 3 1 ORC short 4
2 2
[0205] Application of non-woven ORC tablets (material C-triplicate,
material D-monoplicate) to the liver completely stopped the
bleeding from a bleeding intensity of 4 to 0 (from "moderate" to
"no bleeding") in an 8 mm diameter.times.3 mm depth biopsy punch
size (as shown in Table 4). Application of compressed tablets of
"ORC short" showed almost no expansion of the tablet and the sample
failed to achieve hemostasis (as shown in Table 4).
[0206] Application of non-woven ORC tablets (material
C-monoplicate, material D-duplicate) to the porcine spleen
completely stopped the bleeding from a bleeding intensity of 2/3/4
(the initial bleeding level) to 0 (as shown in Table 5).
Application of compressed tablet of "ORC short" (triplicate was
tested) showed bleeding reduction of 1 or 2.
[0207] The results show that compressed tablets produced from
non-woven ORC materials exhibit higher efficacy over tablets
produced from other ORC materials. These tablets can be potentially
applied in new surgical scenarios and broaden the application scope
for ORC-based material.
[0208] Although the invention has been described in conjunction
with specific embodiments thereof, it is evident that many
alternatives, modifications and variations will be apparent to
those skilled in the art. Accordingly, it is intended to embrace
all such alternatives, modifications and variations that fall
within the spirit and broad scope of the appended claims.
* * * * *